Characteristics and outcomes associated with CD2 and CD25 expression on bone marrow mast cells in patients with systemic mastocytosis.

Not available.

Comparison of prognostic scores according to WHO classification in 170 patients with advanced mastocytosis and C-finding treated with midostaurin.

Advanced systemic mastocytosis (AdvSM) encompasses heterogeneous mastocytosis subtypes and is associated with poor outcomes. Although midostaurin was the first tyrosine kinase inhibitor to be approved for AdvSM patients, long-lasting responses are limited. The mutation-Adjusted Risk Score (MARS), the International Prognostic Scoring System for mastocytosis (IPSM) and the Global Prognostic Score for Systemic Mastocytosis (GPSM) have been established to characterize the outcomes of patients with overall AdvSM. However, given the outcome's dependency on the AdvSM subtype, prognostic characterization within each subtype is critical. We aimed to study the predictive ability using Harrell's concordance index of prognostic scores according to the AdvSM subtype. We conducted a nationwide retrospective study using the French mastocytosis reference center's registry and included all midostaurin-treated patients with C finding. Overall, 170 patients were identified: 46 aggressive SM (ASM), 11 mast cell leukemia (MCL), and 113 SM with associated hematological neoplasm (SM-AHN). All risk scores improved their discriminative value for overall survival (OS) when combined with the AdvSM subtype. The best predictive value was for adjusted MARS (C-index = 0.689), followed by GPSM (C-index = 0.677) and IPSM (C-index = 0.618). In a multivariable analysis, MARS stratification and the AdvSM subtype were both prognostic for OS. Accordingly, five subgroups of patients with AdvSM and a different median OS were identified: 9.9 months for MCL, 24 months for intermediate/high-risk SM-AHN, 33 months for intermediate/high-risk ASM, 58 months for low-risk SM-AHN and was not reached for low-risk ASM (p < 0.001). The AdvSM subtype and the MARS are the most predictive of OS and should prompt specific management.

Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Serious infections in patients with VEXAS syndrome: data from the French VEXAS registry.

INTRODUCTION: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors. METHODS: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models. RESULTS: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV-2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections. CONCLUSION: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency.

Chronological interplay, clinical features, and treatments among patients with cancer and primary Sjögren's syndrome.

OBJECTIVE: While the incidence and type of blood malignancies are well documented amid primary Sjögren's syndrome patients (pSS), data focusing on solid neoplasms are more conflicting. We aimed to describe clinical, pathological, and immunological characteristics of pSS patients with cancers, along with the chronological interplay between the two conditions. METHODS: Outcomes concerning both pSS and cancer were retrospectively collected from Montpellier University Hospital (tertiary center) between 2019 and 2020. pSS characteristics were compared to a control group of pSS patients without cancer. RESULTS: A total of 165 patients with pSS were included: 55 patients with cancer (52 female, mean age 58.4 ± 10.4 years at pSS diagnosis; mean follow-up 10.5 ± 10.1 years, 12 patients had multiple cancers) and 110 controls without cancer. Characteristics of pSS patients with cancers were different from controls mostly for lymphoma prognosis factors. Among the 70 cancers, we recorded 55 solid neoplasms (whom 27 breast cancers and 8 lung cancers, and 82% of adenocarcinomas), with no evidence of disease at the end of follow-up in 85% of them. Among the 15 recorded blood malignancies, ten were lymphomas with an excellent prognosis. Regarding chronological interplay between cancer and pSS, most cancers (43%) were diagnosed close (± 5 years) to pSS diagnosis. Breast cancers were diagnosed before or close to pSS diagnosis (mean delay - 1.8 ± 13.0 years), at an early stage, with only two relapses (no cancer-related death), while lung cancers were diagnosed late after. CONCLUSIONS: The tight chronological interplay between breast cancer and pSS and the intriguing pathological and immunological pattern of pSS in these patients suggest a hypothesis of immune control of cancer.

Prevalence of anti-neutrophil cytoplasmic antibody-associated vasculitis in the south of France, using the capture-recapture method.

OBJECTIVES: This study aimed to estimate the prevalence of ANCA-associated vasculitis (AAV), ie granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), in Southern France in 2018, and evaluate differences among Europeans and non-Europeans. METHODS: This population-based, cross-sectional study used four sources (hospitals, community-based physicians, laboratories, National Health Insurance) to identify adults ≥ 15 years diagnosed with GPA, MPA or EGPA, living in Hérault and Gard in 2018. Cases were defined using the ACR/EULAR classification criteria, and if necessary, the European Medicines Agency algorithm. Prevalence estimates were standardised to the world population and capture-recapture analysis was used to assess the comprehensiveness of the estimation. The influence of geographical origin was evaluated. RESULTS: 202 patients were selected, with 86 cases of GPA (42.6%), 85 cases of MPA (42.1%), and 31 cases of EGPA (15.3%). The standardised prevalence estimates per million inhabitants for 2018 were: 103 (95%CI 84 - 125) for AAV, 48 (95%CI 35 - 64) for GPA, 39 (95%CI 28 - 53) for MPA and 16 (95%CI 9 - 26) for EGPA, 36 (95%CI 25 - 50) for anti-PR3 positive AAV, 46 (95%CI 34 - 61) for anti-MPO positive AAV, and 16 (95%CI 9 - 26) for ANCA-negative AAV. The global estimation of comprehensiveness by capture-recapture analysis was 80.5%. The number of AAV cases was higher for non-European residents (P=0.001), particularly for MPA (P<0.0001). CONCLUSION: We provide a new estimate of AAV prevalence in France and show a higher prevalence of MPA in non-European patients.

Prognosis of immune checkpoint inhibitors-induced myocarditis: a case series.

BACKGROUND: Immune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune-related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening. METHODS: We conducted a multicenter cross-sectional retrospective study with the aim of better characterizing ICI-related myocarditis. Myocarditis diagnosis was based on the recent consensus statement of the International Cardio-Oncology Society. RESULTS: Twenty-nine patients were identified, from six different referral centers. Most patients (55%) were treated using anti-programmed-death 1, rather than ICI combination (35%) or anti-programmed-death-ligand 1 (10%). Transthoracic echocardiography was abnormal in 52% of them, and cardiac magnetic resonance showed abnormal features in 14/24 patients (58%). Eleven patients (38%) were classified as severe. Compared with other patients, they had more frequently pre-existing systemic autoimmune disease (45% vs 6%, p=0.018), higher troponin level on admission (42-fold the upper limit vs 3.55-fold, p=0.001), and exhibited anti-acetylcholine receptor autoantibodies (p=0.001). Seven patients (24%) had myocarditis-related death, and eight more patients died from cancer progression during follow-up. Twenty-eight patients received glucocorticoids, 10 underwent plasma exchanges, 8 received intravenous immunoglobulins, and 5 other immunosuppressants. ICI rechallenge was performed in six patients, with only one myocarditis relapse. DISCUSSION: The management of ICI-related myocarditis may be challenging and requires a multidisciplinary approach. Prognostic features are herein described and may help to allow ICI rechallenge for some patients with smoldering presentation, after an accurate evaluation of benefit-risk balance.

Long-term home parenteral nutrition in systemic sclerosis-related intestinal failure is feasible but unveils occult cardiac disease.

OBJECTIVE: The aim of this study was to compare safety and efficacy of long-term home parenteral nutrition between patients with systemic sclerosis and intestinal failure (IF) and controls with IF from another etiology. METHODS: A retrospective study was conducted in a referral center for systemic sclerosis (SSc) in Montpellier, France. Patients followed between 1985 and 2020 with SSc-related IF were included and compared with control patients with IF from another etiology. The patients included had to be treated for ≥4 wk by home parenteral nutrition (HPN). Primary outcome was occurrence of HPN-related complications. Secondary outcomes included duration of parenteral nutrition, body mass index at 12 mo, and survival. RESULTS: Cumulative duration of HPN was 23 397 catheter days. HPN resulted in body mass index increase in both groups. There was no statistical difference regarding catheter-related bloodstream infections and thrombosis between the groups, despite use of immunosuppressive drugs and autologous hematopoietic stem cell transplantation in patients with SSc. However, the patients with SSc had significantly more HPN-related cardiac overload than the controls (P < 0.0001). Overloads occurred in SSc patients with and without cardiac disease, arguing for comprehensive hemodynamic screening in this condition. CONCLUSION: Long-term HPN in SSc-related IF is feasible but unveils occult cardiac disease.

Immune-mediated diseases involving central and peripheral nervous systems.

BACKGROUND AND PURPOSE: In addition to combined central and peripheral demyelination, other immune diseases could involve both the central nervous system (CNS) and peripheral nervous system (PNS). METHODS: To identify immune-mediated diseases responsible for symptomatic combined central/peripheral nervous system involvement (ICCPs), we conducted a multicentric retrospective study and assessed clinical, electrophysiological, and radiological features of patients fulfilling our ICCP criteria. RESULTS: Thirty patients (20 males) were included and followed during a median of 79.5 months (interquartile range [IQR] = 43-145). The median age at onset was 51.5 years (IQR = 39-58). Patients were assigned to one of four groups: (i) monophasic disease with concomitant CNS/PNS involvement including anti-GQ1b syndrome (acute polyradiculoneuropathy + rhombencephalitis, n = 2), checkpoint inhibitor-related toxicities (acute polyradiculoneuropathy + encephalitis, n = 3), and anti-glial fibrillary acidic protein astrocytopathy (subacute polyradiculoneuropathy and meningoencephalomyelitis with linear gadolinium enhancements, n = 2); (ii) chronic course with concomitant CNS/PNS involvement including paraneoplastic syndromes (ganglionopathy/peripheral hyperexcitability + limbic encephalitis, n = 4); (iii) chronic course with sequential CNS/PNS involvement including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (polyradiculoneuropathy + strokes, n = 2), histiocytosis (polyradiculoneuropathy + lepto-/pachymeningitis, n = 1), and systemic vasculitis (multineuropathy + CNS vasculitis/pachymeningitis, n = 2); and (iv) chronic course with concomitant or sequential CNS/PNS involvement including combined central and peripheral demyelination (polyradiculoneuropathy + CNS demyelinating lesions, n = 10) and connective tissue diseases (ganglionopathy/radiculopathy/multineuropathy + limbic encephalitis/transverse myelitis/stroke, n = 4). CONCLUSIONS: We diagnosed nine ICCPs. The timing of central and peripheral manifestations and the disease course help determine the underlying immune disease. When antibody against neuroglial antigen is identified, CNS and PNS involvement is systematically concomitant, suggesting a common CNS/PNS antigen and a simultaneous disruption of blood-nerve and blood-brain barriers.

Hospitalizations for infections in primary Sjögren's syndrome patients: a nationwide incidence study.

BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune disease with increased risk of infections. Here, we assessed whether pSS patients were at higher risk of hospitalization for community and opportunistic infections. METHODS: We selected newly hospitalized pSS patients between 2011 and 2018, through a nationwide population-based retrospective study using the French Health insurance database. We compared the incidence of hospitalization for several types of infections (according to International Classification for Disease codes, ICD-10) between pSS patients and an age- and sex-matched (1:10) hospitalized control group. We calculated adjusted Hazard Ratios (aHR, 95% CI) adjusted on socio-economic status, past cardiovascular or lung diseases and blood malignancies factors. RESULTS: We compared 25 661 pSS patients with 252 543 matched patients. The incidence of hospitalizations for a first community infection was increased in pSS patients [aHR of 1.29 (1.22-1.31), p < .001]. The incidence of hospitalization for bronchopulmonary infections was increased in pSS patients [aHR of 1.50 (1.34-1.69), p < .001, for pneumonia]. Hospitalizations for pyelonephritis and intestinal infections were increased [aHR of 1.55 (1.29-1.87), p < .001 and 1.18 (1.08-1.29), p < .001, respectively]. Among opportunistic infections, only zoster, and mycobacteria infections (tuberculosis and non-tuberculous) were at increased risk of hospitalization [aHR of 3.32 (1.78-6.18), p < .001; 4.35 (1.41-13.5), p = .011 and 2.54 (1.27-5.06), p = .008, respectively]. CONCLUSIONS: pSS patients are at higher risk of hospitalization for infections. The increased risk of hospitalization for mycobacterial infections illustrates the potential bilateral relationship between the two conditions. Vaccination against respiratory pathogens and herpes zoster virus may help prevent some hospitalizations in pSS patients.KEY MESSAGESPrimary Sjögren's syndrome (pSS) increases hospitalization risk for community infections: bronchopulmonary, skin, dental, ear-nose-throat, intestinal infections and pyelonephritis.Hospitalizations for zoster and mycobacterial infections are also increased in this population.Dedicated preventive measures and vaccination campaigns could decrease the burden of infections in pSS patients.

Pulmonary hypertension reported with immune checkpoint inhibitors: a pharmacovigilance study.

Immune checkpoint inhibitors (ICI) restore immune response against cancer cells that can lead to immune-related adverse effects. While cardiovascular immune-related adverse effects are known to be associated with checkpoint inhibitors, recent case reports have raised concerns about the potential association with pulmonary hypertension (PH). By using the global pharmacovigilance database VigiBase, we investigated the onset of PH associated with ICI and propose a comprehensive description of the 42 cases of PH reported with ICI recorded in this database. Through this study and review of the cases published in the literature, we discuss the possible link between PH and ICI in the context of cancer in order to better understand this rare but potentially fatal event.

Sjögren syndrome overlapping with ANCA-associated vasculitis: Four additional cases and systematic literature review.

OBJECTIVES: Sjögren's syndrome (SS) and ANCA-associated vasculitis (AAV) have distinct clinical presentation and evolution, with paucity of reports on overlap syndrome. We aimed to better characterize this entity. METHODS: We report four additional cases from the Montpellier university hospital. We also performed a systematic literature review, according to PRISMA guidelines, in Medline, Embase, Web of science, Cochrane Library, and grey literature. Demographic, clinical, and paraclinical data on SS and AAV were analysed. RESULTS: A total of 3133 articles was identified in databases, with 2695 articles screened for eligibility. After exclusion, we had 30 articles on 40 patients to analyse, in addition to 4 patients from our local recruitment (44 patients overall). Patients were female in 81.8%, with median age at AAV onset of 63.5 years. All patients but one presented with SS before, or concomitantly to the diagnosis of AAV, with a median delay of 12 months between both diagnoses. AAV predominantly had renal involvement (35/44 patients, 79.5%), anti-MPO antibodies being the most frequent (35 patients), even in patients presenting with granulomatosis with polyangiitis. We observed significantly more Raynaud phenomenon and associated auto-immune diseases in the group of non-granulomatous AAV (10 patients versus 1, p = 0.015 and 8 patients versus 0, p = 0.013, respectively). CONCLUSIONS: This is the largest descriptive study on the association between SS and AAV, providing information on this challenging diagnosis and interplay between these two diseases. Particular attention should be paid in the first months after diagnosis, given the specific complications and outcomes of each disease.

[Influenza A: H1N1 post-viral membranoproliferative glomerulonephritis occurring in aggressive systemic mastocytosis: Case report and literature review]. / Glomérulonéphrite membrano-proliférative post-grippale chez un patient atteint de mastocytose systémique agressive : observation commentée et revue de la littérature.

Systemic mastocytosis is characterised by tissular infiltration and a cytokine storm due to mast cells excessive proliferation and activation. Herein, we report an extraordinary case of AH1N1 influenza post-viral glomerulonephritis occurring in the course of an aggressive systemic mastocytosis with an associated hematological neoplasm. Because of a multisystemic involvement including the liver and lungs, we treated mastocytosis with midostaurin (multiple inhibitor of kinase protein), anti H1/H2 blockers and dexamethasone as first line treatment. One month later and despite vaccination, he developed a severe acute lung injury with respiratory distress due to AH1N1 influenza in association with the nephrotic syndrome. Kidney biopsy disclosed a membranoproliferative glomerulonephritis that was successfully treated with mycophenolate mofetil. Only a few cases of influenza post-viral or post-vaccination glomerulonephritis are documented in the medical literature. This is an exceptional association of uncommon conditions occurring within only a few months in the same patient.

Cardiovascular Events, Sleep Apnoea, and Pulmonary Hypertension in Primary Sjögren's Syndrome: Data from the French Health Insurance Database.

Primary Sjögren's syndrome (pSS) is an autoimmune disease, associated with a high risk of lymphoma. Mounting evidence suggests that cardiovascular morbidity and mortality are higher in patients with pSS, although data are heterogeneous. The aim of this study was to assess whether pSS patients are at higher risk of hospitalisation for cardiovascular events (CVEs), venous thromboembolic events (VTEs), pulmonary hypertension (PH), and sleep apnoea syndrome (SAS). Through a nationwide population-based retrospective study using the French health insurance database, we selected new-onset pSS in-patients hospitalised between 2011 and 2018. We compared the incidence of CVEs (ischemic heart diseases (IHDs), strokes, and heart failure), SAS, VTEs, and PH with an age- and sex-matched (1:10) hospitalised control group. The calculations of adjusted hazard ratios (aHR) included available confounding factors. We studied 25,661 patients hospitalised for pSS compared with 252,543 matched patients. The incidence of hospitalisation for IHD, SAS, and PH was significantly higher in pSS patients (aHR: 1.20 (1.06-1.34); p = 0.003, aHR: 1.97 (1.70-2.28); p < 0.001, and aHR: 3.32 (2.10-5.25); p < 0.001, respectively), whereas the incidence of stroke, heart failure, and VTE was the same between groups. Further prospective studies are needed to confirm these results and to explore the pathophysiological mechanisms involved.

Cancer incidence in primary Sjögren's syndrome: Data from the French hospitalization database.

The relationship between cancer and primary Sjögren's syndrome (pSS) is uncertain. While the increased risk of hematological malignancies is well-known, data on the comparative incidence of solid neoplasms is conflicting. This study aimed to explore the associations between cancer and pSS. This nationwide population-based retrospective study from the French health insurance database (PMSI) evaluated patients hospitalized with new-onset pSS from 2011 to 2018 against age- and sex-matched hospitalized controls (1:10). The incidence of hematological malignancies and solid neoplasms was compared between the two groups. Mortality and multiple cancer incidence were also evaluated. Adjusted Hazard Ratios (aHR) calculations included confounding factors, such as low socioeconomic status. Among 25,661 hospitalized patients with pSS versus 252,543 matched patients (median follow-up of 3.96 years), we observed a higher incidence rate of lymphomas (aHR, 1.97 [95% CI, 1.59-2.43]), Waldenström macroglobulinemia (aHR, 10.8 [6.5-18.0]), and leukemia (aHR, 1.61 [1.1-2.4]). Thyroid cancer incidence was higher (aHR, 1.7 [1.1-2.8]), whereas bladder and breast cancer incidences were lower (aHR, 0.58 [0.37-0.89] and 0.60 [0.49-0.74], respectively). pSS patients with breast cancer exhibited a lower mortality rate. A limitation was that the database only encompasses hospitalized patients, and immunological and histological details are not listed. We confirmed the increased risk of hematological malignancies and thyroid cancers among patients with pSS. The lower risk of breast cancer suggests a role of hormonal factors and raises questions of the concept of immune surveillance within breast tissue. Epidemiological and translational studies are required to elucidate the relationships between pSS and cancer.

Lung Fibrosis Is Improved by Extracellular Vesicles from IFNγ-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a severe autoimmune disease for which mesenchymal stromal cells (MSCs)-based therapy was reported to reduce SSc-related symptoms in pre-clinical studies. Recently, extracellular vesicles released by MSCs (MSC-EVs) were shown to mediate most of their therapeutic effect. Here, we aimed at improving their efficacy by increasing the MSC-EV dose or by IFNγ-priming of MSCs. METHODS: small size (ssEVs) and large size EVs (lsEVs) were recovered from murine MSCs that were pre-activated using 1 or 20 ng/mL of IFNγ. In the HOCl-induced model of SSc, mice were treated with EVs at day 21 and sacrificed at day 42. Lung and skin samples were collected for histological and molecular analyses. RESULTS: increasing the dose of MSC-EVs did not add benefit to the dose previously reported to be efficient in SSc. By contrast, IFNγ pre-activation improved MSC-EVs-based treatment, essentially in the lungs. Low doses of IFNγ decreased the expression of fibrotic markers, while high doses improved remodeling and anti-inflammatory markers. IFNγ pre-activation upregulated iNos, IL1ra and Il6 in MSCs and ssEVs and the PGE2 protein in lsEVs. CONCLUSION: IFNγ-pre-activation improved the therapeutic effect of MSC-EVs preferentially in the lungs of SSc mice by modulating anti-inflammatory and anti-fibrotic markers.